Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the p53-MDM2 protein-protein interaction

A series of thio-benzodiazepine p53-MDM2 inhibitors were designed and synthesized based on the principle of bioisosterism. Most of the thio-benzodiazepines had nanomolar to micromolar affinity toward MDM2. Particularly, compounds 8a (K-i = 0.52 mu M) and 8f (K-i = 0.32 mu M) showed binding activity comparable to the positive drug nutlin-3a (K-i = 0.23 mu M). Meanwhile, compound 8j exhibited excellent antitumor activity against the U-2 OS human osteosarcoma cell line with an IC50 value of 1.06 mu M, which was about 23 times higher than that of nutlin-3a. The docking model also successfully predicted that this class of compounds mimicked three p53 critical residues binding to MDM2. The thio-benzodiazepines represent a promising class of non-peptide inhibitors of the p53-MDM2 interaction. (C) 2011 Published by Elsevier Masson SAS.